The sweet taste of true synergy: positive allosteric modulation of the human sweet taste receptor

Servant, Guy; Tachdjian, Catherine; Li, Xiaodong; Karanewsky, Donald S.

doi:10.1016/j.tips.2011.06.007

Cited by 64 publications

(57 citation statements)

References 40 publications

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“…48,49 Both subunits are G proteincoupled receptors with large aminoterminal domains which form orthosteric venus flytrap binding motifs and seven transmembrane segments that contain allosteric binding sites. 50 All sweet tasting substances appear to activate the TAS1R2/TAS1R3 heterodimer. 42 In order to investigate if the human sweet taste receptor heteromer is sensitive to the 2-furaldehydes, functional calcium imaging experiments were performed with 7 and 6 in HEK293 FlpIn T-Rex Gα 15 G i3 / hTAS1R2 cells.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Sensomics Analysis of Taste Compounds in Balsamic Vinegar and Discovery of 5-Acetoxymethyl-2-furaldehyde as a Novel Sweet Taste Modulator

Hillmann

Mattes

Brockhoff

et al. 2012

J. Agric. Food Chem.

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Sensory-directed fractionation of traditional balsamic vinegar of Modena (TBV) led to the identification of the sweet-bitter tasting hexose acetates 6-O-acetyl-α/β-d-glucopyranose and 1-O-acetyl-β-d-fructopyranose as well as the previously unknown sweetness modulator 5-acetoxymethyl-2-furaldehyde. Taste re-engineering experiments and sensory time-intensity studies confirmed 5-acetoxymethyl-2-furaldehyde to contribute to the typical long-lasting sweet taste quality of TBV. Moreover, the response of the sweet taste receptor to this furaldehyde was verified by means of a functional hTAS1R2/hTAS1R3 receptor assay. Quantitative analysis of a total of 59 nonvolatile sensometabolites and taste modulators revealed higher concentrations of the sweet-modulating 5-acetoxymethyl-2-furaldehyde, nonvolatile organic acids and polyphenols such as wood-derived ellagitannins, and lower concentrations of acetic acid in the premium quality TBV when compared to balsamic vinegar of Modena (BV). Quantitative monitoring of sensometabolites throughout TBV manufacturing, followed by agglomerative hierarchical clustering and sensomics heatmapping, gave molecular insights into the taste alterations occurring during TBV maturation.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Sensomics Analysis of Taste Compounds in Balsamic Vinegar and Discovery of 5-Acetoxymethyl-2-furaldehyde as a Novel Sweet Taste Modulator

Hillmann

Mattes

Brockhoff

et al. 2012

J. Agric. Food Chem.

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“…CaSR is assumed to constitutively dimerize through disulfide bonding between cystein residues 120 and 131, an event that underlies the proper functioning of this receptor. Allosteric regulation is one of the important characteristics of CaSR, similar to the taste receptors and metabotrophic glutamate receptors [28,33]. Allosteric modulators acting at six teric modulator of CaSR; (2) CaSR shows at least two different active conformations, a calcium-bound form that couples with both Gq/11 and Gi/o, and a calcium and autoantibody-bound form that couples to Gq/11 specifically (Fig.…”

Section: Characteristics Of Casrmentioning

confidence: 99%

Biased agonism: a novel paradigm in G protein-coupled receptor signaling observed in acquired hypocalciuric hypercalcemia [Review]

Makita

Iiri

2014

Endocr J

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Abstract. The classical model of G protein-coupled receptor (GPCR) activation is the two-state model, in which the GPCR exists in equilibrium between an active and inactive state. Based on this model, GPCR ligands have been classified as agonists, inverse agonists, or antagonists depending on their actions in shifting this equilibrium. Recently, however, accumulating evidence has indicated that GPCRs may exist in multiple active and inactive conformational states. In this situation, each ligand recognizes and stabilizes a specific conformation of the GPCR, leading to a set of specific biological effects. Based on this new model, a unique agonist or a combination of the usual agonist and an allosteric modulator may enable activation of a specific signaling pathway via a GPCR that activates multiple signals (biased agonism, functional selectivity). The calcium-sensing receptor autoantibody that we have identified in the serum of a patient with acquired hypocalciuric hypercalcemia (AHH) is the first example of a biased allosteric modulator of a GPCR working in a pathophysiological context. Our findings may indicate the presence of physiological allosteric modulators and provide new directions for the future drug development.

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“…Allosteric modulation has been studied most extensively in non-gustatory GPCRs (e.g. [35, 36, 37]), but PAMs have been proposed to explain how ligands that do not taste sweet can enhance sensitivity to receptor agonists that do taste sweet [15–17]. Because lactisole acts as an inverse agonist [8, 9], sweeteners can bind to and produce conformational changes within the receptor even as their ability to excite it is blocked.…”

Section: Discussionmentioning

confidence: 99%

“…Whether an agonist can suppress or enhance the lactisole SWT may depend on how the conformational change it produces interacts with the conformational change caused by lactisole’s dissociation from the TMD. The fact that in most C GPCRs PAMs bind to the TMD [38] demonstrates the potential for conformational interactions of this kind to take place. The abrupt and complete block of the SWT by sweeteners sampled after exposure to lactisole was also agonist-dependent and might also be explained by allosteric interactions, as conformational changes produced by agonists may interact with conformational changes produced by dissociating lactisole.…”

Section: Discussionmentioning

confidence: 99%

“…An investigation in experiment 3 of a preliminary observation that the SWT was perceived on the tongue tip when the tongue was dipped into flowing water provided evidence of the importance of water flow for the SWT as well as support for the importance of receptor potency in the suppression of SWT. The findings from all 3 experiments are discussed within the context of the current model of the SWT and the possibility that allosteric modulation, a fundamental characteristic of GCPR function [13–17], plays a significant role in the ability of sweeteners to modulate the lactisole SWT.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential modulation of the lactisole ‘Sweet Water Taste’ by sweeteners

Alvarado¹,

Nachtigal²,

Slack³

et al. 2017

PLoS ONE

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Pre-exposure to taste stimuli and certain chemicals can cause water to have a taste. Here we studied further the ‘sweet water taste’ (SWT) perceived after exposure to the sweet taste inhibitor lactisole. Experiment 1 investigated an incidental observation that presenting lactisole in mixture with sucrose reduced the intensity of the SWT. The results confirmed this observation and also showed that rinsing with sucrose after lactisole could completely eliminate the SWT. The generalizability of these findings was investigated in experiment 2 by presenting 5 additional sweeteners before, during, or after exposure to lactisole. The results found with sucrose were replicated with fructose and cyclamate, but the 3 other sweeteners were less effective suppressors of the SWT, and the 2 sweeteners having the highest potency initially enhanced it. A third experiment investigated these interactions on the tongue tip and found that the lactisole SWT was perceived only when water was actively flowed across the tongue. The same experiment yielded evidence against the possibility that suppression of the SWT following exposure to sweeteners is an aftereffect of receptor activation while providing additional support for a role of sweetener potency. Collectively these results provide new evidence that complex inhibitory and excitatory interactions occur between lactisole and agonists of the sweet taste receptor TAS1R2-TAS1R3. Receptor mechanisms that may be responsible for these interactions are discussed in the context of the current model of the SWT and the possible contribution of allosteric modulation.

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The sweet taste of true synergy: positive allosteric modulation of the human sweet taste receptor

Cited by 64 publications

References 40 publications

Sensomics Analysis of Taste Compounds in Balsamic Vinegar and Discovery of 5-Acetoxymethyl-2-furaldehyde as a Novel Sweet Taste Modulator

Sensomics Analysis of Taste Compounds in Balsamic Vinegar and Discovery of 5-Acetoxymethyl-2-furaldehyde as a Novel Sweet Taste Modulator

Biased agonism: a novel paradigm in G protein-coupled receptor signaling observed in acquired hypocalciuric hypercalcemia [Review]

Differential modulation of the lactisole ‘Sweet Water Taste’ by sweeteners

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